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Journal of Immunology Research
Volume 2014, Article ID 103780, 8 pages
http://dx.doi.org/10.1155/2014/103780
Review Article

Potential Benefits of Therapeutic Use of β2-Adrenergic Receptor Agonists in Neuroprotection and Parkinson’s Disease

1Theralogics, Inc., 1829 E. Franklin Street, Chapel Hill, NC 27514-5861, USA
2School of Dentistry, University of Alberta, 7020 Katz Group Centre, Edmonton, AB, Canada T6G 2R3
3North Carolina Oral Health Institute, School of Dentistry, The University of North Carolina at Chapel Hill, Manning Dr. & Columbia Street, Campus Box 7450, Chapel Hill, NC 27599-7450, USA

Received 29 June 2013; Revised 3 December 2013; Accepted 4 December 2013; Published 19 January 2014

Academic Editor: David Kaplan

Copyright © 2014 Lynda Peterson et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The β2-adrenergic receptor (β2AR) is a seven-transmembrane (7TM) G-protein coupled receptor that is expressed on cells of the pulmonary, cardiac, skeletal muscle, and immune systems. Previous work has shown that stimulation of this receptor on immune cells has profound effects on the regulatory activity of both adaptive and innate immune cells. This review examines the functional dichotomy associated with stimulation of β2AR and microglial cells. As well, recent studies targeting these receptors with long-acting agonists are considered with respect to their therapeutic potential in management of Parkinson’s disease.

1. Introduction

Neurodegenerative disorders, such as Alzheimer’s, Huntington’s, and Parkinson’s disease, are characterized by the progressive loss of the structure and function of neurons. Specifically, Parkinson’s disease is characterized by the death of dopaminergic (DA) neurons (cell groups A8 and A9) in the midbrain, substantia nigra (SN), and striatum. Over time, this leads to impaired motor skills, shaking, slowness of movement, and postural instability, well known symptoms of PD. In addition, many patients experience dementia and executive dysfunction. A recent study of an unselected population-representative cohort () highlights the poor prognosis of PD patients as evidenced by a 55% mortality rate within 10 years of diagnosis [1]. Of the survivors, 68% and 46% had postural instability and dementia, respectively; 23% had not yet progressed to either of these irreversible disease milestones.

Since the late 1960s, levodopa has been a key treatment and is the gold standard nearly 50 years later [2]. Converted to dopamine within the brain, it is used to control the motor symptoms of the disease but is ineffective with respect to dementia, freezing, or autonomic functions. A host of other treatments have been developed centered primarily around maintaining or increasing dopamine concentrations within the brain, such as dopamine agonists, MAO B inhibitors, catechol o-methyltransferase (COMT) inhibitors, anticholinergics, and amantadine. Stem cell transplant therapy and deep brain stimulation have also been explored with varying results.

What is known about neurodegenerative disorders in general and in Parkinson’s disease in particular is that the progressive nature is in part associated with chronic inflammation and microglial activation [3]. Although a variety of triggers, including inherited genetic mutations and environmental toxins, can initiate the advent of neurodegeneration, inflammation is now recognized as an underlying mechanism that drives the progressive nature of Parkinson’s disease [48]. As such, this review will examine the research exploring potential therapeutic targets aimed at abrogating the inflammatory dysfunction.

2. The Dysfunctional Immune System in Parkinson’s Disease

Well over two decades ago, it was first recognized that activated microglia and neuroinflammation were associated with the SN lesions of PD patients when observed postmortem [8, 9]. Additionally, an accidental human neurotoxin model of Parkinson’s disease also implicated activated microglia and chronic neuroinflammation in progressive loss of SN neurons [10, 11]. In this report, a group of drug users were exposed at relatively young ages to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a contaminant in street-drugs. Each developed progressive Parkinsonian symptoms years after exposure. Postmortem analyses indicated the presence of neuroinflammation, activated microglia, and active neurodegeneration in the SN up to 15 years after systemic exposure to the MPTP contaminant [11]. Similar findings resulted from experiments with a long-term primate model of MPTP-induced SN degeneration [12]. These studies demonstrate that once a trigger initiates neuroinflammation in the SN, the condition can persist for long periods causing progressive loss of DA neurons.

Microglia are the innate immunity cells resident in the brain and are a major source of proinflammatory factors, such as tumor necrosis factor α (TNFα), interleukin-1 β (IL-1β), interleukin-6 (IL-6), reactive oxygen species (ROS), and nitric oxide as well as many others [3]. Microglia can also play beneficial roles in maintaining brain homeostasis and produce factors involved in neural cell survival, proliferation, growth, and motility. Microglia also secrete anti-inflammatory factors, including transforming growth factor β (TGF-β). As active immune sentinels, microglia have been observed in vivo to continually extend processes to probe their microenvironment even when in the so-called “resting” state [13]. However, after insult, microglia are rapidly activated, migrate to the site of injury, and phagocytose injured and dying cells [13].

In Parkinson’s disease, it is these activated microglia that become self-propelling mediators of neuronal cell death leading to chronic inflammation. Once a trigger induces initial injury or death of DA neurons, activated microglia perpetuate the death of more neurons through the cyclic processes of pro-inflammatory reactive microgliosis [3, 14, 15]. In this manner, microglia mediate the progressive loss of DA neurons giving rise to characteristic postmortem PD reports of activated microglia, chronic inflammation, and loss of DA neurons within the SN. We have developed a model for the etiology of progressive Parkinson’s disease (Figure 1). In this model, we believe that a direct neurotoxin, such as MPTP, or an inflammatory trigger, such as LPS, can lead to the direct or indirect activation of microglia. Animal models of neurodegeneration triggered by toxin exhibit similar progressive destruction of the SN.

103780.fig.001
Figure 1: Model of neurodegeneration attributed to reactive microgliosis in Parkinson’s disease.

3. β2-Adrenergic Receptors

Microglia express high levels of β2AR at the cell surface [16]. Interestingly, several studies found that depletion of the endogenous β2AR agonist, norepinephrine (NE), caused increased microglial-induced neuroinflammation and that administration of NE protects cortical neurons from microglial-induced cell death [17, 18]. Furthermore, NE administration dose-dependently blocked microglial expression of the inflammatory mediators NOS2 and IL-1β, and these anti-inflammatory effects could be completely reversed by coapplication of the β2AR-specific antagonist, ICI-118,551 [18]. Together, these findings implicate β2AR as playing a key regulatory role in microglia activation.

Specifically, in humans the β2-adrenergic receptor (β2AR) is a 413 amino acid long glycoprotein that is a member of the seven-transmembrane (7TM) family of G-protein coupled receptors [19, 20]. Adrenergic receptors are subdivided into three groups (β1, β2, and β3) which are expressed in a variety of cell and tissue types, with the β2AR subtype classically occurring in the various cells of the pulmonary, cardiac, skeletal muscle, and immune systems [19]. Therapies that modulate β2AR responses are well documented for uses in treating asthma and other respiratory diseases, as well as hypertension and angina.

4. β2AR Agonists

Beta-adrenergic receptor agonists are a group of drugs that are mimetics of endogenously occurring catecholamines, including epinephrine, norepinephrine, and dopamine. Agonists can be either direct interacting with the receptors or indirect in that they do not stimulate receptor activation but induce the release of endogenous catecholamines. There are multiple synthetic β2AR agonists which act mainly in the smooth muscle and endothelial cells of the pulmonary system, vasculature, bronchial tree, colon, and uterus. β2AR agonists have two functional forms: short-acting agonists used predominantly as fast-acting bronchodilators in treating asthma and other acute bronchial disorders, and long-acting agonists that are used to manage and control chronic, long-term bronchial diseases, such as chronic obstructive pulmonary disease (COPD). β2AR agonists have also been used to prevent premature labor by administration systemically to act upon the smooth muscle of the uterus.

4.1. Short-Acting versus Long-Acting β2AR Agonists

The molecular characteristics of the particular agonist determine the mode of interactions with β2AR and ultimately the manner in which downstream effects are generated. Agonists that have hydrophilic properties are able to access the receptor directly from the aqueous extracelluar environment. These agonists thus have relatively rapid effects and are generally termed “short-acting” due to the rapid onset and short duration of their stimulatory activity upon the receptor. Long-acting agonists are generally lipophilic and are taken up into the cell membrane where they slowly leach-out to access the β2AR over longer periods of time, thus producing more long lasting effects [19, 21]. Studies have shown that the β-ARs are also stereospecific and that this enantiomeric specificity can be important for agonist-induced functional responses from the stimulation of the receptor [22]. Furthermore, stereoselectivity by the receptor can determine the immunomodulatory effects of β2AR stimulation, especially with regards to the response of activated macrophages [19, 22]. However, studies have also shown in a model of cerebroischemic stroke that while two enantiomers of a lipophilic β2AR-agonist provide neuroprotection by activating astrocytes and inducing production of neurotropic factors, one racemate might also induce more adverse side-effects [23, 24].

5. β2AR Agonists in Neuroprotection

Long-acting β2AR agonists that are typically used as bronchodilators in the treatment of asthma have also shown to have trophic effects in tissue culture models of CNS injury [25, 26]. Up-regulation of β2ARs after brain damage in vivo is associated with astrocyte activation and neuroprotection [27, 28]. Induction of neurotrophic growth factors and astrocyte activation by long-acting β2AR-agonists has been found to mediate neuroprotection in several in vivo models of neuronal damage [23, 29, 30]. β2ARs are also expressed in microglial cells and have been shown to mediate the inhibition of microglia activation [31]. However, β2AR antagonists are reported in another study to block IL-6 production and acute inflammatory response, as well as to provide neuroprotection in a model of hemorrhagic stroke [32]. In contrast, the same antagonist (butoxamine) did not have any neuroprotective effect in a model of focal cerebral ischemia [30]. In fact, in this model butoxamine actually abrogated the neuroprotection provided by treatment with β2AR agonists [30]. It is suggested that the different results for neuroprotection have more to do with the two different models of stroke brain-damage and the mechanisms responsible for the damage [33]. Additionally, in a rat model of traumatic brain injury (TBI), stimulation of β2AR with agonist decreased brain function impairment and improved recovery after injury [34]. This latter study found that the agonist stimulated neuroprotection after TBI correlated with decreased levels of blood glutamate levels which are typically elevated in response to injury and are generally neurotoxic [34]. However, a major caveat in interpreting all of these studies is that the models required pretreatment with the β2ARs agonists (or antagonist) in order for neuroprotection. In contrast, in an LPS-stimulated chronic model of Parkinson’s disease, treatment with the long-acting agonist salmeterol after initiation of the disease prevented neurotoxicity via inhibition of reactive microglia [35].

6. β2AR Agonists in the Treatment of Parkinson’s Disease

In 2011, we looked at the effects of both the short-acting β2AR agonist, salbutamol, and a variety of long-acting β2AR agonists, including salmeterol, on the survival of DA neurons after induction of inflammation in different disease models of Parkinson’s disease [35]. In mixed cell-cultures composed of primary mesencephalic neurons and glial cells that were treated with LPS, the long-acting agonists protected DA neurons from inflammation-induced cytotoxicity as did salbutamol. However, a short-acting agonist was able to confer neuro-cell protection only at much higher concentrations. In contrast to these beneficial effects in an inflammation-based model of neurotoxicity, we found that salmeterol treatment had less pronounced protective effects in a similar mixed cell model which featured induction of DA neuron death by MPTP. The MPTP metabolite MPP+ mediates direct toxicity on the neurons themselves and this neuronal death leads to the induction of reactive microgliosis, whereas LPS-induced neurotoxicity is mediated by the direct action of LPS on microglial cells leading to their production of inflammatory mediators, which leads to neuronal death and the continuing cycle of reactive microgliosis [3, 36]. However, when tested in two in vivo models of PD, the LPS-stimulated long-term mouse model and the acute MPTP model, salmeterol also exhibited some neuroprotective effects either by pretreatment (in the LPS-induced model) or by treatment with salmeterol post MPTP-injections respectively. These results suggested to us that long-acting β2AR agonists, such as salmeterol, might be developed for their anti-inflammatory effects to attenuate the progressive loss of DA neurons characteristic in Parkinson’s disease and improve motor activity in patients. Additional studies using non-MPTP models of PD should help determine whether use of agonists such as salmeterol could prove beneficial in the management of Parkinson’s disease.

7. β2AR Agonists and Signaling Pathways

In addition to their role in stimulating G-protein coupled signaling, β2AR agonists also transduce signals from the receptor through its association with β-arrestins [37]. In addition to mediating receptor desensitization through blocking G-protein coupling with β2AR [38], β- arrestin can also link β2AR to the activation of other signaling pathways, such as the MAPK signaling cascade and the kinase complex that regulates activation/inhibition of the transcription factor, NF-κB [37, 39]. Earlier studies found that the inflammatory effects of β2AR agonists at high concentrations were mediated through β2AR-induced cAMP production [4042]. However, Qian and colleagues showed that, in primary murine-microglia cultures, the addition of low concentrations of salmeterol inhibited the LPS-induced production of inflammatory mediators, such as reactive oxygen species (ROS), TNFα, and nitric oxide (NO) [35]. This inhibition is β2AR and β-arrestin dependent but cAMP independent [35]. Thus, low doses of salmeterol might inhibit inflammation and promote neuroprotection by regulating receptor association with β-arrestins and β-arrestins-mediated function in other signaling pathways such as NF-κB pathway and the MAPK signaling cascade.

7.1. Anti-Inflammation and NF-κB

It has been shown that β2AR agonists, at low concentrations, stimulate anti-inflammatory effects by negative regulation of the transcription factor NF-κB [39]. β-arrestin2 is a binding partner of IκBa which is an inhibitor of NF-κB activation [39]. NF-κB is a ubiquitously expressed transcription factor that regulates transcription of genes involved in immunity and inflammation [43]. Five members of the NF-κB/Rel family of proteins, including p50, p52, p65 (RelA), c-Rel, and RelB, are expressed in mammalian cells. These NF-κB proteins form various homo- and hetero-dimers in the cell cytosol where they are held in the inactive state by association with inhibitory proteins called IκBs [44]. A variety of signaling pathways converge at a kinase complex (NF-κB-inducing kinase/NIK and IκB kinase/IKKα-IKKβ-IKKγ) that regulates NF-κB activation by controlling the association with IκBs. When activated, the catalytic subunits of this kinase complex (IKKα and IKKβ) phosphorylate IκBα and target it for degradation. Degradation of IκBα releases NF-κB and unmasks the nuclear signal domain which targets NF-κB translocation to the nucleus where it binds to the κB site, and is functionally active in transcription of inflammatory genes. In this way, regulation of NF-κB transcription activity depends upon interaction with IκB, and in turn, proteins such as β-arrestin that bind the IκB kinase complex and regulate IκB are critical for regulating both IκB and NF-κB. Low-dose salmeterol has been shown to inhibit NF-κB activation suppressing its translocation to the nucleus [35]. Thus the beneficial effects of salmeterol might be exerted at least in part through β-arrestin-mediated control of NF-κB.

7.2. Anti-Inflammation and MAPK

Activation of β2AR can also stimulate the MAPK signaling cascade via a G-protein-independent but β-arrestin-dependent mechanism [45]. Previous studies also showed that activation of β2AR with high concentrations of salmeterol ( M to  M) induced the MAPK signaling pathway leading to increased phosphorylation of ERK1/2 and resulting in proinflammatory effects in macrophages and primary microglia [46]. However, this proinflammatory effect is mediated through activation of the cAMP pathway, although it is PKA-independent. Of key interest is that these same high doses of salmeterol increased neurotoxicity in mixed cell cultures and that this was mediated through increased NADPH oxidase activity through an ERK-dependent pathway [47]. Conversely, low concentrations of salmeterol greatly reduced the LPS-stimulated phosphorylation/activation of components of the MAPK, namely, ERK1/2, p38, and JNK [35]. Thus, lower concentrations of the β2AR agonist apparently produce anti-inflammatory effects by inhibiting both MAPK cascade signaling and NF-κB activation. Further supporting evidence is that low-dose salmeterol inhibits a common upstream effector for both MAPK and NF-κB; TGF-beta activated kinase 1 (TAK1) has been shown to be a key regulatory component in various signaling pathways involved in immunity and inflammation [48]. Both MAPK and NF-κB are downstream targets of TAK1 which is also the convergent effector for LPS/TRL- and TNFα-stimulated inflammation. Low doses of salmeterol ( M and  M) can inhibit the activating phosphorylation of TAK1 in primary microglia. This suggests that the inhibitory effect on MAPK signaling and NF-κB activation involves inhibition of TAK1. However, the link(s) between inhibition of TAK1 and the β-arrestin-dependent anti-inflammatory effects of low-dose salmeterol has yet to be determined.

7.3. Anti-Inflammatory Effects of Low-Dose Salmeterol

Previous results have shown that β2AR agonists are known to activate MAPKs via both Gs-dependent and Gs-independent mechanisms. A Gs-independent increase in phosphorylation of ERK occurres following high doses of salmeterol treatment in RAW264 macrophage cells and primary microglia cells [46], which mediates a proinflammatory and neurotoxic effect [47]. Conversely, much lower doses of salmeterol ( M) have no proinflammatory effects but rather show dramatic inhibition of MAPK molecules ERK, JNK, and p38 in LPS-activated primary microglia. Although both effects appear to work independently of PKA activation, the proinflammatory effect of high-dose salmeterol is through the activation of the cAMP/EPAC pathway, and the inhibitory effect of low-dose salmeterol is independent of cAMP induction as well as PKA and EPAC activity. Rather, it appears as though the inhibitory activity of salmeterol is due to the activation of β-arrestin-2, which functionally inhibits both NF-κB [39] and MAP-K [49]. In addition, low doses of salmeterol have a significant inhibitory effect on the LPS-mediated activation of NF-κB and the production of inflammatory mediators normally under NF-κB and MAP-K regulation, such as TNF-α and NO. However, this anti-inflammatory action of salmeterol may be selective only for certain proinflammatory pathways in microglial cells because low-dose salmeterol is able to inhibit the activation of superoxide production by LPS but not by PMA (which functions through the PKC pathway). Therefore, it appears that low-dose salmeterol can be potently but selectively anti-inflammatory in microglial cells by targeting the NF-κB and MAPK signaling pathways following pro-inflammatory activation, as depicted in the model (Figure 2).

103780.fig.002
Figure 2: Molecular mechanism of the inhibitory function of salmeterol-mediated β2AR activation.
7.4. β-Arrestin-Biased Agonism

β-arrestin-biased agonism has been shown for a variety of β2AR agonists [37]. These agonists show preferential activation of noncanonical signaling that favors β-arrestin-mediated signals from the receptor over cAMP/PKA-mediated pathways. However, in the study by Drake and colleagues, salmeterol was not amongst these β-arrestin-biased agonists. Significantly, these studies used salmeterol at receptor-saturating μM concentrations and showed that at these doses, salmeterol stimulated the production of cAMP and instigated cAMP-induced signaling [37]. Qian et al., in a 2009 study, found much the same results, that at high concentration, salmeterol increased the production of cAMP and downstream factors such NADPH oxidase activity [47]. These results are in sharp contrast to the effects of low concentrations of the same agonist, namely, that to  M salmeterol does not stimulate increased cAMP and its downstream effectors but activates a β-arrestin-mediated reduction in some of these same downstream signaling events [35]. A distinction between the β-arrestin biased agonists and the nonbiased agonists reported by Drake et al. is the existence of a different structural characteristic between the two groups (the β-arrestin biased group all have an a-carbon ethyl substituent moiety lacking in the nonbiased group) [37]. It is interesting that Qian and colleagues essentially instigated the same β-arrestin-favored signaling by drastically reducing doses of salmeterol, a supposedly nonbiased β2AR agonist. Thus, β2AR agonists provide wide possibilities for utilizing biased signaling properties, from whatever mechanism of the bias, to develop therapeutic potential in novel disease backgrounds. In the case of inflammatory diseases such as Parkinson’s disease, agonists, such as salmeterol, might be used therapeutically not only for their ability to inhibit inflammation and stop progressive neurotoxicity, but also to stimulate preferential signaling cascades that foster neurogenesis.

Salmeterol applied at concentrations from 1 nM to 100 nM has been shown to promote proliferation in adult rat dentate gyrus-derived neural precursor cells (ADP) [50]. Furthermore, it has also been found that neural progenitor cell proliferation is not necessarily cAMP-CREB-dependent [51]. Given that low doses of salmeterol preferentially stimulate β-arrestin signaling effectors as opposed to cAMP signaling events, the potential for neurogenic effects is intriguing at the least.

8. Concluding Remarks

The neuroprotective effects of β2AR activation by higher doses of β2AR agonists have been reported in other conditions, such as amyotrophic lateral sclerosis [52], cerebral ischemia [53], and spinal cord injury-induced locomotor dysfunction [54]. Although it is not yet clear how the β2AR agonists exhibit all of these neuroprotective properties, several studies have suggested that β2AR agonists function to stimulate glutathione-dependent antioxidant processes from nerve cells [30]. Meanwhile, others have reported that neurotrophic factors from activated astrocytes induced by β2AR agonists contribute to neuroprotection [55]. We propose that the major neuroprotective activity of β2AR agonists in Parkinson’s disease models is due to their anti-inflammatory properties. It is clear that the effectiveness of the β2AR agonist, salmeterol, and the other long-acting β2AR agonists at low concentrations is due to their anti-inflammatory effect on microglia and not to a direct protective effect on DA-neurons or through an astrocyte-dependent effect. Given the effectiveness of these compounds at such low concentrations in inhibiting inflammatory responses, they appear to have significant potential in regulating CNS inflammation and the treatment of chronic inflammatory disorders of CNS.

Abbreviations

β2AR:β2-adrenergic receptor
DA:Dopaminergic
IL:Interleukin
MPTP:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
ROS:Reactive oxygen species
SN:Substantia nigra
TNFα:Tumor necrosis factor α.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

  1. C. H. Williams-Gray, S. L. Mason, J. R. Evans et al., “The CamPaIGN study of Parkinson's disease: 10-year outlook in an incident population-based cohort,” Journal of Neurology, Neurosurgery, and Psychiatry, vol. 84, no. 11, pp. 1258–1264, 2013. View at Publisher · View at Google Scholar
  2. O. Rascol, A. Lozano, M. Stern, and W. Poewe, “Milestones in Parkinson's disease therapeutics,” Movement Disorders, vol. 26, no. 6, pp. 1072–1082, 2011. View at Publisher · View at Google Scholar · View at Scopus
  3. M. L. Block and J.-S. Hong, “Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism,” Progress in Neurobiology, vol. 76, no. 2, pp. 77–98, 2005. View at Publisher · View at Google Scholar · View at Scopus
  4. A. L. Bartels and K. L. Leenders, “Neuroinflammation in the pathophysiology of Parkinson's disease: evidence from animal models to human in vivo studies with [11C]-PK11195 PET,” Movement Disorders, vol. 22, no. 13, pp. 1852–1856, 2007. View at Publisher · View at Google Scholar · View at Scopus
  5. W. Dauer and S. Przedborski, “Parkinson's disease: mechanisms and models,” Neuron, vol. 39, no. 6, pp. 889–909, 2003. View at Publisher · View at Google Scholar · View at Scopus
  6. H.-M. Gao, J. Jiang, B. Wilson, W. Zhang, J.-S. Hong, and B. Liu, “Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson's disease,” Journal of Neurochemistry, vol. 81, no. 6, pp. 1285–1297, 2002. View at Publisher · View at Google Scholar · View at Scopus
  7. H.-M. Gao and J.-S. Hong, “Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression,” Trends in Immunology, vol. 29, no. 8, pp. 357–365, 2008. View at Publisher · View at Google Scholar · View at Scopus
  8. P. L. McGeer, S. Itagaki, B. E. Boyes, and E. G. McGeer, “Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains,” Neurology, vol. 38, no. 8, pp. 1285–1291, 1988. View at Google Scholar · View at Scopus
  9. P. L. McGeer, S. Itagaki, H. Akiyama, and E. G. McGeer, “Rate of cell death in parkinsonism indicates active neuropathological process,” Annals of Neurology, vol. 24, no. 4, pp. 574–576, 1988. View at Google Scholar · View at Scopus
  10. J. W. Langston, I. Irwin, E. B. Langston, and L. S. Forno, “1-Methyl-4-phenylpyridinium ion (MPP+): identification of a metabolite of MPTP, a toxin selective to the substantia nigra,” Neuroscience Letters, vol. 48, no. 1, pp. 87–92, 1984. View at Google Scholar · View at Scopus
  11. J. W. Langston, L. S. Forno, J. Tetrud, A. G. Reeves, J. A. Kaplan, and D. Karluk, “Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure,” Annals of Neurology, vol. 46, no. 4, pp. 598–605, 1999. View at Google Scholar
  12. P. L. McGeer, C. Schwab, A. Parent, and D. Doudet, “Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration,” Annals of Neurology, vol. 54, no. 5, pp. 599–604, 2003. View at Publisher · View at Google Scholar · View at Scopus
  13. A. Nimmerjahn, F. Kirchhoff, and F. Helmchen, “Neuroscience: resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo,” Science, vol. 308, no. 5726, pp. 1314–1318, 2005. View at Publisher · View at Google Scholar · View at Scopus
  14. M. K. McCoy and M. G. Tansey, “TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease,” Journal of Neuroinflammation, vol. 5, article 45, 2008. View at Publisher · View at Google Scholar · View at Scopus
  15. L. Qian and P. M. Flood, “Microglial cells and Parkinson's disease,” Immunologic Research, vol. 41, no. 3, pp. 155–164, 2008. View at Publisher · View at Google Scholar · View at Scopus
  16. K. F. Tanaka, H. Kashima, H. Suzuki, K. Ono, and M. Sawada, “Existence of functional β1- and β2-adrenergic receptors on microglia,” Journal of Neuroscience Research, vol. 70, no. 2, pp. 232–237, 2002. View at Publisher · View at Google Scholar · View at Scopus
  17. M. T. Heneka, E. Galea, V. Gavriluyk et al., “Noradrenergic depletion potentiates β-amyloid-induced cortical inflammation: implications for Alzheimer's disease,” Journal of Neuroscience, vol. 22, no. 7, pp. 2434–2442, 2002. View at Google Scholar · View at Scopus
  18. J. L. M. Madrigal, D. L. Feinstein, and C. Dello Russo, “Norepinephrine protects cortical neurons against microglial-induced cell death,” Journal of Neuroscience Research, vol. 81, no. 3, pp. 390–396, 2005. View at Publisher · View at Google Scholar · View at Scopus
  19. M. Johnson, “Beta2 -adrenoceptors: mechanisms of action of beta2-agonists,” Paediatric Respiratory Reviews, vol. 2, no. 1, pp. 57–62, 2001. View at Publisher · View at Google Scholar · View at Scopus
  20. B. K. Kobilka, R. A. F. Dixon, and T. Frielle, “cDNA for the human β2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 84, no. 1, pp. 46–50, 1987. View at Google Scholar · View at Scopus
  21. M. Johnson, “The β-adrenoceptor,” American Journal of Respiratory and Critical Care Medicine, vol. 158, no. 5, pp. S146–S153, 1998. View at Google Scholar · View at Scopus
  22. C. A. Izeboud, R. M. Vermeulen, A. Zwart, H.-P. Voss, A. S. J. P. Van Miert, and R. F. Witkamp, “Stereoselectivity at the β2-adrenoceptor on macrophages is a major determinant of the anti-inflammatory effects of β2-agonists,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 362, no. 2, pp. 184–189, 2000. View at Publisher · View at Google Scholar · View at Scopus
  23. C. Culmsee, V. Junker, S. Thal et al., “Enantio-selective effects of clenbuterol in cultured neurons and astrocytes, and in a mouse model of cerebral ischemia,” European Journal of Pharmacology, vol. 575, no. 1-3, pp. 57–65, 2007. View at Publisher · View at Google Scholar · View at Scopus
  24. I. Semkova, M. Schilling, P. Henrich-Noack, A. Rami, and J. Krieglstein, “Clenbuterol protects mouse cerebral cortex and rat hippocampus from ischemic damage and attenuates glutamate neurotoxicity in cultured hippocampal neurons by induction of NGF,” Brain Research, vol. 717, no. 1-2, pp. 44–54, 1996. View at Publisher · View at Google Scholar · View at Scopus
  25. C. Culmsee, R. K. Stumm, M. K.-H. Schäfer, E. Weihe, and J. Krieglstein, “Clenbuterol induces growth factor mRNA, activates astrocytes, and protects rat brain tissue against ischemic damage,” European Journal of Pharmacology, vol. 379, no. 1, pp. 33–45, 1999. View at Publisher · View at Google Scholar · View at Scopus
  26. P. Follesa and I. Mocchetti, “Regulation of basic fibroblast growth factor and nerve growth factor mRNA by β-adrenergic receptor activation and adrenal steroids in rat central nervous system,” Molecular Pharmacology, vol. 43, no. 2, pp. 132–138, 1993. View at Google Scholar · View at Scopus
  27. C. Hodges-Savola, S. D. Rogers, J. R. Ghilardi, D. R. Timm, and P. W. Mantyh, “Beta-adrenergic receptors regulate astrogliosis and cell proliferation in the central nervous system in vivo,” Glia, vol. 17, no. 1, pp. 52–62, 1996. View at Google Scholar
  28. P. W. Mantyh, S. D. Rogers, C. J. Allen et al., “β2-adrenergic receptors are expressed by glia in vivo in the normal and injured central nervous system in the rat, rabbit, and human,” Journal of Neuroscience, vol. 15, no. 1 I, pp. 152–164, 1995. View at Google Scholar · View at Scopus
  29. C. Culmsee, I. Semkova, and J. Krieglstein, “NGF mediates the neuroprotective effect of the β2-adrenoceptor agonist clenbuterol in vitro and in vivo: evidence from an NGF-antisense study,” Neurochemistry International, vol. 35, no. 1, pp. 47–57, 1999. View at Publisher · View at Google Scholar · View at Scopus
  30. V. Junker, A. Becker, R. Hühne et al., “Stimulation of β-adrenoceptors activates astrocytes and provides neuroprotection,” European Journal of Pharmacology, vol. 446, no. 1–3, pp. 25–36, 2002. View at Publisher · View at Google Scholar · View at Scopus
  31. H. Fujita, J. Tanaka, N. Maeda, and M. Sakanaka, “Adrenergic agonists suppress the proliferation of microglia through β2-adrenergic receptor,” Neuroscience Letters, vol. 242, no. 1, pp. 37–40, 1998. View at Publisher · View at Google Scholar · View at Scopus
  32. H. Kato, M. Kawaguchi, S. Inoue, K. Hirai, and H. Furuya, “The effects of β-adrenoceptor antagonists on proinflammatory cytokine concentrations after subarachnoid hemorrhage in rats,” Anesthesia and Analgesia, vol. 108, no. 1, pp. 288–295, 2009. View at Publisher · View at Google Scholar · View at Scopus
  33. C. Culmsee, “Targeting β2-adrenoceptors for neuroprotection after cerebral ischemia: is inhibition or stimulation best?” Anesthesia and Analgesia, vol. 108, no. 1, pp. 3–5, 2009. View at Publisher · View at Google Scholar · View at Scopus
  34. A. Zlotnik, Y. Klin, B. F. Gruenbaum et al., “β2 Adrenergic-mediated reduction of blood glutamate levels and improved neurological outcome after traumatic brain injury in rats,” Journal of Neurosurgical Anesthesiology, vol. 24, no. 1, pp. 30–38, 2012. View at Publisher · View at Google Scholar · View at Scopus
  35. L. Qian, H. Wu, S.-H. Chen et al., “β2-adrenergic receptor activation prevents rodent dopaminergic neurotoxicity by inhibiting microglia via a novel signaling pathway,” Journal of Immunology, vol. 186, no. 7, pp. 4443–4454, 2011. View at Publisher · View at Google Scholar · View at Scopus
  36. L. Qian, S. T. Kai, S.-J. Wei et al., “Microglia-mediated neurotoxicity is inhibited by morphine through an opioid receptor-independent reduction of NADPH oxidase activity,” Journal of Immunology, vol. 179, no. 2, pp. 1198–1209, 2007. View at Google Scholar · View at Scopus
  37. M. T. Drake, J. D. Violin, E. J. Whalen, J. W. Wisler, S. K. Shenoy, and R. J. Lefkowitz, “β-arrestin-biased agonism at the β2-adrenergic receptor,” The Journal of Biological Chemistry, vol. 283, no. 9, pp. 5669–5676, 2008. View at Publisher · View at Google Scholar · View at Scopus
  38. L. M. Luttrell and R. J. Lefkowitz, “The role of β-arrestins in the termination and transduction of G-protein-coupled receptor signals,” Journal of Cell Science, vol. 115, no. 3, pp. 455–465, 2002. View at Google Scholar · View at Scopus
  39. D. S. Witherow, T. R. Garrison, W. E. Miller, and R. J. Lefkowitz, “β-arrestin inhibits NF-κB activity by means of its interaction with the NF-κB inhibitor IκBα,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 23, pp. 8603–8607, 2004. View at Publisher · View at Google Scholar · View at Scopus
  40. C.-H. Hung, Y.-T. Chu, Y.-M. Hua et al., “Effects of formoterol and salmeterol on the production of Th1- and Th2-related chemokines by monocytes and bronchial epithelial cells,” European Respiratory Journal, vol. 31, no. 6, pp. 1313–1321, 2008. View at Publisher · View at Google Scholar · View at Scopus
  41. A. Severn, N. T. Rapson, C. A. Hunter, and F. Y. Liew, “Regulation of tumor necrosis factor production by adrenaline and β-adrenergic agonists,” Journal of Immunology, vol. 148, no. 11, pp. 3441–3445, 1992. View at Google Scholar · View at Scopus
  42. T. van der Poll, J. Jansen, E. Endert, H. P. Sauerwein, and S. J. H. van Deventer, “Noradrenaline inhibits lipopolysaccharide-induced tumor necrosis factor and interleukin 6 production in human whole blood,” Infection and Immunity, vol. 62, no. 5, pp. 2046–2050, 1994. View at Google Scholar · View at Scopus
  43. P. A. Baeuerle and D. Baltimore, “IκB: a specific inhibitor of the NF-κB transcription factor,” Science, vol. 242, no. 4878, pp. 540–546, 1988. View at Google Scholar · View at Scopus
  44. A. S. Baldwin Jr., “The NF-κB and IκB proteins: new discoveries and insights,” Annual Review of Immunology, vol. 14, pp. 649–681, 1996. View at Google Scholar · View at Scopus
  45. S. K. Shenoy, M. T. Drake, C. D. Nelson et al., “β-arrestin-dependent, G protein-independent ERK1/2 activation by the β2 adrenergic receptor,” The Journal of Biological Chemistry, vol. 281, no. 2, pp. 1261–1273, 2006. View at Publisher · View at Google Scholar · View at Scopus
  46. K. S. Tan, A. G. Nackley, K. Satterfield, W. Maixner, L. Diatchenko, and P. M. Flood, “β2 adrenergic receptor activation stimulates pro-inflammatory cytokine production in macrophages via PKA- and NF-κB-independent mechanisms,” Cellular Signalling, vol. 19, no. 2, pp. 251–260, 2007. View at Publisher · View at Google Scholar · View at Scopus
  47. L. Qian, X. Hu, D. Zhang et al., “β2 adrenergic receptor activation induces microglial NADPH oxidase activation and dopaminergic neurotoxicity through an ERK-dependent/protein kinase A-independent pathway,” Glia, vol. 57, no. 15, pp. 1600–1609, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. H. Sakurai, “Targeting of TAK1 in inflammatory disorders and cancer,” Trends in Pharmacological Sciences, vol. 33, no. 10, pp. 522–530, 2012. View at Google Scholar
  49. M. Tipping, Y. Kim, P. Kyriakakis, M. Tong, S. Y. Shvartsman, and A. Veraksa, “β-arrestin Kurtz inhibits MAPK and Toll signalling in Drosophila development,” The EMBO Journal, vol. 29, no. 19, pp. 3222–3235, 2010. View at Publisher · View at Google Scholar · View at Scopus
  50. T. Masuda, S. Nakagawa, S. Boku et al., “Noradrenaline increases neural precursor cells derived from adult rat dentate gyrus through beta2 receptor,” Progress in Neuro-Psychopharmacology & Biological Psychiatry, vol. 36, no. 1, pp. 44–51, 2012. View at Publisher · View at Google Scholar · View at Scopus
  51. S. Nakagawa, J.-E. Kim, R. Lee et al., “Regulation of Neurogenesis in Adult Mouse Hippocampus by cAMP and the cAMP Response Element-Binding Protein,” Journal of Neuroscience, vol. 22, no. 9, pp. 3673–3682, 2002. View at Google Scholar · View at Scopus
  52. Y. D. Teng, H. Choi, W. Huang et al., “Therapeutic effects of clenbuterol in a murine model of amyotrophic lateral sclerosis,” Neuroscience Letters, vol. 397, no. 1-2, pp. 155–158, 2006. View at Publisher · View at Google Scholar · View at Scopus
  53. C. Culmsee, V. Junker, W. Kremers, S. Thal, N. Plesnila, and J. Krieglstein, “Combination therapy in ischemic stroke: synergistic neuroprotective effects of memantine and clenbuterol,” Stroke, vol. 35, no. 5, pp. 1197–1202, 2004. View at Publisher · View at Google Scholar · View at Scopus
  54. R. J. Zeman, H. Peng, Y. Feng, H. Song, X. Liu, and J. D. Etlinger, “β2-adrenoreceptor agonist-enhanced recovery of locomotor function after spinal cord injury is glutathione dependent,” Journal of Neurotrauma, vol. 23, no. 2, pp. 170–180, 2006. View at Publisher · View at Google Scholar · View at Scopus
  55. I. Semkova and J. Krieglstein, “Neuroprotection mediated via neurotrophic factors and induction of neurotrophic factors,” Brain Research Reviews, vol. 30, no. 2, pp. 176–188, 1999. View at Publisher · View at Google Scholar · View at Scopus